The HNRC, established on 6/1/89, is a multi-institutional and multidisciplinary collaborative NIMH Center, pooling the efforts of investigators from the University of California, San Diego (UCSD), the Veterans Affairs Medical Center (VAMC), the Naval Medical Center, and the Research Institute of Scripps Clinic (RISC). The overall goals of the HNRC are to define the etiology, pathogenesis, features, course, and outcomes of HIV-1 involvement of the central nervous system. To achieve these goals, the HNRC is organized as eight core investigations (Medical, Virology, Neurology, Neuropsychology, Psychiatry, Imaging, Neuropathology, Outcomes) and six distinct projects (SPECT, MR Information Processing, CMV, Molecular Characterization of Neurotropic Variants, Immune Control of HIV Expression in Monocytes/Macrophages, Neuroendocrine). These are linked via the Statistics and Data Management Core, and coordinated by the Administrative Core. These interlocking studies will examine 475 HIV+ men and women at various disease stages and 125 relevant HIV-controls every 6-12 months, and relate antemortem data to postmortem neuropathology from an estimated 150 brains. In its initial funding period the HNRC determined that mild cognitive disorders occur in 30% of CDC "A" HIV+persons, 44% of "B" and 55% of "C", with neuropsychological profiles strongly reminiscent of a "subcortical" disorder. Quantitated imaging studies have determined that there are gradual reductions in volumes of subcortical gray structures and gradual increase in white manner corresponding perhaps to loss of neurones in deep gray and inflammatory changes in white matter. These imaging changes also are seen during the asymptomatic phase. Neuropathologic studies have shown immunocytochemical evidence of HIV in 65% of persons dying with AIDS, although only about 30% had "classical" HIV encephalopathy. There is evidence both for pre-synaptic and post-synaptic neuropathology. Presence in CSF of rapidly replicating syncytia forming T lymphotropic virus may be associated with greater likelihood of cognitive disorder. Additionally, preliminary research indicates that the molecular "signature" of HIV derived from brain may differ from that derived from peripheral macrophages. Proposed for the competitive renewal are experiments related to better understanding of the characteristics of HIV-1, as well as host characteristics that may foster CNS complications; also, studies are proposed to define more precisely the temporal and anatomic progression of HIV in the brain, with detailed antemortem/postmortem comparisons. Finally, the personal and social "costs" of mild cognitive disorder will be examined by careful analysis of occupational and social functioning of HIV- infected persons with varying severities of neurocognitive disturbance.